Patients enrolled in NIH prospective studies of transfusion-associated hepatitis have been followed long-term to determine the persistence of hepatitis C virus (HCV) infection and the chronic consequences of that infection. Eighty-five percent of patients infected with HCV became chronic carriers and 15 percent resolved their infection usually within 1 year of onset. The vast majority of patients with persistent viremia have some evidence of chronic hepatitis based on serial alanine aminotransferase (ALT) determinations and liver biopsy. Of those biopsied, approximately 20 percent have histologic evidence of cirrhosis, though only half of those patients have had clinical evidence of cirrhosis. Liver-related mortality within the first 2 decades of followup has been 4 percent. These NIH patients were incorporated into a multi-center study of 568 persons with transfusion-associated non-A, non-B hepatitis (predominantly hepatitis C) and 984 matched controls who were transfused, but did not develop hepatitis. After an average followup of 18 years, all cause mortality was 51 percent in the hepatitis group and 52 percent in the controls (NS). There was a slight increase in liver-related mortality in the hepatitis group (3.3 percent vs. 1.4 percent, p=. 03). Seventy-one percent of the deaths due to liver disease occurred in patients with associated chronic alcoholism. Twenty-year morbidity follow-up of 103 HCV-positive individuals shows that 77 percent have persistent infection, 17 percent have recovered, but maintain antibody to HCV and 6 percent show no serologic or molecular evidence of their prior HCV infection. Less than 15 percent have developed cirrhosis; in the absence of cirrhosis, there is virtually no clinical evidence of this longstanding HCV infection.